Homopurine:homopyrimidine stretches of dsDNA can form triple helices with homopyrimidine oligonucleotides. Triple helical structures prevent transcription and translation across their sequences. We have designed several homopyrimidine oligonucleotides (ONs) which target specific HIV genes (gag, pol, tat, rev, nef) and modified them to prevent degradation by cellular nucleases. We tested the ability of these ONs to suppress HIV-1 infection of a lymphocyte cell line (H9). Infected cells treated with 10 to 50 nanomolar concentrations of ON produced from 50 - 90% less viral p24 antigen than control infected cells, in a dose-responsive manner. No cell toxicity or effect on cell doubling time was observed at these low concentrations of ON. DNA-PCR assays on treated cells showed decreased amounts of viral DNA relative to untreated cells. These results suggest that the ONs are functioning as triple helix- formers and could be an effective antiviral technology. We are continuing these studies with 1) primary human peripheral blood lymphocytes and 2) higher concentrations of ONs. This work has been accepted as an abstract for slide presentation at the 1992 ICAAC meeting to be held in October.